The invention relates to oral medicinal forms with reproducible disintegration time and release of the active ingredient fatifloxacin (1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(3-methylpiperazin-1-yl)-4 -oxoquinoline-3-carboxylic acid) or pharmaceutically acceptable salts or hydrates thereof, and to a process for their preparation.
Formulations in the form of solid individual medicinal forms, e.g. tablets, are prepared by compression. Tablets represent the most common and most important solid medicinal form in medical care. Examples which may be listed here are sublingual tablets, swallowing tablets, buccal tablets, effervescent tablets, ophthalmic tablets, quick-release tablets or coated tablets. These are prepared by compression from finely crystalline, powdered or granular drugs, normally with the addition of auxiliary substances.
The physical and chemical properties of the individual active ingredients are decisive for the preparation of tablets. The density, water content, crystalline form, surface structure, particle size, solubility, flow properties, hygroscopic nature and quality level of the active ingredient in question may be mentioned here. In particular, the water content, particle size, crystalline form and solubility of the active ingredients in question have a greater effect on the process for the preparation of tablets of high pharmaceutical quality (D. Chulia, M. Deleuil; Powder Technology and Pharmaceutical Process, 1994).
Tablets are prepared by the compression of powders or granules. Granulation is understood as meaning the conversion of small particles of powder to larger agglomerates. Tablets prepared from granules often have a greater mechanical strength than tablets compressed from powder. This is brought about by the uneven and rough surface of the granules; these have larger contact areas, giving rise to an increase in the adhesive forces. In the case of wet granulation, the granules are prepared from the primary particles with the aid of a liquid. The liquid, which can be selected from the group consisting of water, alcohols and polar or non-polar hydrocarbon compounds, usually also contains so-called binders, e.g. polyvinylpyrrolidone, pregelatinized starch or hydroxypropyl cellulose.
If tablets consist of granules, a distinction is made with this type of formulation between an inner phase and at least one outer phase. The inner phase comprises mostly the active ingredient and other auxiliary substances. This part is granulated in a wet or dry process and referred to as the inner phase of the ultimate compressed tablet. In the wet granulation process a defined amount of liquid is added to the mixture of substances and the whole is granulated. The ingredients of the so-called outer phase are auxiliary substances from the group consisting of binders, disintegration aids, lubricants and/or fillers. The two phases are mixed and then compressed to a solid medicinal form.
The disintegration time of tablets and the associated release of active ingredient is an important indicator of bioavailability in the human body.
The disintegration of tablets is a test method for providing evidence about a well-defined medicinal form. To determine the disintegration, tablets are placed in an apparatus, the main part of which generally consists of a rigid frame with a perforated bottom containing e.g. 6 cylindrical glass test tubes of fixed dimensions. Each tube can be fitted with a disc of a translucent plastic material or comparable materials which have specific orifices and V-shaped indentations. The test tubes are held vertical by an upper and a lower plate which can be made of plastic. On the underside there is a stainless steel wire gauze with a mesh size of 2 mm. The apparatus is moved uniformly up and down 28 to 32 times a minute by means of a motor. The apparatus is suspended in a vessel containing a suitable liquid. The amount of liquid present in the vessel should be such that the wire gauze is still immersed below the liquid surface at the highest point of its travel and is still above the bottom of the vessel at its lowest point, and the mouths of the tubes remain above the liquid surface. The liquid should be kept at a temperature of 36.degree. C. to 38.degree. C. The requirements are satisfied if disintegration occurs after a defined period of time (European Pharmacopoeia, Ph. Eur.). Examples of liquid media which can be used are water or artificial digestive juice at a given temperature (European Pharmacopoeia, Ph. Eur.).
Studies on the release of active ingredients are used to determine the dissolution rate of active ingredients from solid oral medicinal forms like tablets or capsules, as only the dissolved drug can be absorbed in the gastrointestinal tract. These studies are carried out under in vitro conditions, e.g. in water, artificial gastric juice with a pH of e.g. 1.2 or artificial intestinal juice with a pH of e.g. 6.8, at a temperature of 37.degree. C., over a defined period of time (European Pharmacopoeia, Ph. Eur.). Vane stirrer or rotary basket apparatuses are used. Both of these consist of a vessel, a stirrer and a thermostatted bath. The vessel is covered with a flanged lid to prevent the test liquid from evaporating. There is a sampling orifice so that the concentration of the drug can be determined over time.
Formulations of solid medicinal forms with the active ingredient gatifloxacin or pharmaceutically acceptable salts or hydrates have already been described in EP-B 0 230 295. It was found that reproducible disintegration times and active ingredient release of the known tablet formulations are difficult to guarantee (cf. Table 1, Examples 1 to 4), the disintegration times of these solid formulations varying within a range of 3 minutes to 600 minutes.